EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance

C. Depner, H. zum Buttel, N. Böğürcü, A. M. Cuesta, M. R. Aburto, S. Seidel, F. Finkelmeier, F. Foss, J. Hofmann, K. Kaulich, S. Barbus, M. Segarra, G. Reifenberger, B. K. Garvalov, T. Acker () and A. Acker-Palmer ()
Additional contact information
C. Depner: Institute of Neuropathology, University of Giessen
H. zum Buttel: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
N. Böğürcü: Institute of Neuropathology, University of Giessen
A. M. Cuesta: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
M. R. Aburto: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
S. Seidel: Institute of Neuropathology, University of Giessen
F. Finkelmeier: Institute of Neuropathology, University of Giessen
F. Foss: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
J. Hofmann: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
K. Kaulich: Heinrich Heine University of Düsseldorf, Düsseldorf and German Cancer Consortium (DKTK)
S. Barbus: German Cancer Research Center (DKFZ)
M. Segarra: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt
G. Reifenberger: Heinrich Heine University of Düsseldorf, Düsseldorf and German Cancer Consortium (DKTK)
B. K. Garvalov: Institute of Neuropathology, University of Giessen
T. Acker: Institute of Neuropathology, University of Giessen
A. Acker-Palmer: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.

Date: 2016
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DOI: 10.1038/ncomms12329

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